Ready to use diclofenac stick packs

ABSTRACT

Ready to use liquid formulations of diclofenac potassium are disclosed which are particularly well suited for packaging in stick-packs.

FIELD OF THE INVENTION

This invention pertains to a ready to use, liquid, orally administered formulations containing 50 mg of diclofenac potassium with unexpected chemical stability and palatability.

BACKGROUND OF THE INVENTION

Diclofenac potassium ([2-(2,6-dichlorophenyl)amino]benzeneacetate, potassium salt) is a potent NSAID (non-steroidal anti-inflammatory drug) used therapeutically for inflammatory conditions and pain management. The solubility of diclofenac potassium (pKa=3.9) is pH dependent. It is sparingly soluble at acidic pH, and the amount of the active substance dissolved in buffered solutions increases with the increasing pH of the dissolution aqueous medium. The stability of Diclofenac and its salts is well known in the solid state: Diclofenac acid and its salts are in fact characterized by a chemical stability when they are taken in their solid state. When dissolved in water, in contrast, the molecule could be expected to undergo fast and irreversible oxidative degradation according to the auto-oxidation pathway in FIG. 1.

Diclofenac is sold in various dosage forms, including tablets (Cataflam®), powders for oral solution (Cambia®), gel-caps (Zipsor®), patches (Flector®), and gels (Voltaren®). Other dosage forms are described, inter alia, in WO 2006/133954 (Reiner et al.), WO 1997/044023 (Reiner et al.), and WO 2003/043600 (Reiner et al.). Given its wide spectrum of action and therapeutic benefit, additional dosage forms are needed for convenience of the patient and additional therapeutic uses.

SUMMARY OF INVENTION

The inventors have developed a liquid, single dose, ready to use formulation containing diclofenac potassium as a unique active ingredient with the aim of obtaining a palatable and a chemically and physically stable water based oral solution. The stability of this unique liquid dosage form has been demonstrated in different primary packaging and under different storage conditions by preliminary stability studies, which showed that the impurities content conforms to rigorous pharmaceutical specifications even under accelerated conditions intended to induce degradation.

Therefore, one embodiment the invention provides a ready to use diclofenac formulation comprising: (a) diclofenac or a pharmaceutically acceptable salt thereof; (b) an alkalizing agent imparting a pH of from about 7 to about 10 to the formulation, optionally comprising potassium or sodium bicarbonate; and (c) a sugar-based aqueous means for solubilizing and stabilizing said formulation; wherein the formulation is optionally a liquid.

In another embodiment the invention provides a liquid diclofenac formulation in a ready to use stick pack comprising: (a) a therapeutically effective amount of diclofenac or a pharmaceutically acceptable salt thereof; (b) an alkalizing agent imparting a pH of from about 7 to about 10 to the formulation, optionally comprising potassium or sodium bicarbonate; and (c) a sugar-based aqueous means for solubilizing and stabilizing said formulation.

In still another embodiment the invention provides a method of treating a condition selected from pain and migraine in a patient in need thereof comprising administering to said patient a therapeutically effective amount of any of the ready to use diclofenac formulations of the present invention, preferably one comprising: (a) diclofenac or a pharmaceutically acceptable salt thereof; (b) an alkalizing agent imparting a pH of from about 7 to about 10 to the formulation, optionally comprising potassium or sodium bicarbonate; and (c) a sugar-based aqueous means for solubilizing and stabilizing said formulation, wherein the formulation is optionally provided as a liquid formulation in a ready to use stick pack.

Additional advantages of the invention are set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawing, which is incorporated in and constitutes a part of this specification, illustrates several embodiments of the invention and together with the description serves to explain the principles of the invention.

FIG. 1 depicts various auto-oxidation pathways for diclofenac potassium.

DETAILED DESCRIPTION Definitions and Use of Terms

As used in this specification and in the claims which follow, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

As used in this specification and in the claims which follow, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. When an element is described as comprising a plurality components, steps or conditions, it will be understood that the element can also be described as comprising any combination of such plurality, or “consisting of” or “consisting essentially of” the plurality or combination of components, steps or conditions.

“Therapeutically effective amount” means that amount which, when administered to a human for supporting or affecting a metabolic process, or for treating or preventing a disease, is sufficient to cause such treatment or prevention of the disease, or supporting or affecting the metabolic process.

When ranges are given by specifying the lower end of a range separately from the upper end of the range, or specifying particular numerical values, it will be understood that a range can be defined by selectively combining any of the lower end variables, upper end variables, and particular numerical values that is mathematically possible. In like manner, when a range is defined as spanning from one endpoint to another, the range will be understood also to encompass a span between and excluding the two endpoints.

When used herein the term “about” will compensate for variability allowed for in the pharmaceutical industry and inherent in products in this industry, such as differences in product strength due to manufacturing variation and time-induced product degradation. The term allows for any variation which in the practice of good manufacturing practices would allow the product being evaluated to be considered therapeutically equivalent or bioequivalent in humans to the recited strength of a claimed product.

In the context of the present invention insofar as it relates to any of the disease conditions recited herein, the term “treatment” means to reduce the occurrence of a symptom or condition, or to relieve or alleviate at least one symptom associated with such condition, or to slow or reverse the progression of such condition, or to manage or affect the metabolic processes underlying such condition. Within the meaning of the present invention, the terms also denote to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.

The phrase “acceptable” as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a subject (e.g., a mammal such as a human).

DISCUSSION

In one embodiment the invention provides a ready to use diclofenac formulation comprising: (a) diclofenac or a pharmaceutically acceptable salt thereof; (b) an alkalizing agent imparting a pH of from about 7 to about 10 to the formulation, optionally comprising potassium or sodium bicarbonate; and (c) a sugar-based aqueous means for solubilizing and stabilizing said formulation; wherein the formulation is optionally a liquid.

In another embodiment the invention provides a liquid diclofenac formulation in a ready to use stick pack comprising: (a) a therapeutically effective amount of diclofenac or a pharmaceutically acceptable salt thereof; (b) an alkalizing agent imparting a pH of from about 7 to about 10 to the formulation, optionally comprising potassium or sodium bicarbonate; and (c) a sugar-based aqueous means for solubilizing and stabilizing said formulation.

In still another embodiment the invention provides a method of treating a condition selected from pain and migraine in a patient in need thereof comprising administering to said patient a therapeutically effective amount of any of the ready to use diclofenac formulations of the present invention, preferably one comprising: (a) diclofenac or a pharmaceutically acceptable salt thereof; (b) an alkalizing agent imparting a pH of from about 7 to about 10 to the formulation, optionally comprising potassium or sodium bicarbonate; and (c) a sugar-based aqueous means for solubilizing and stabilizing said formulation, wherein the formulation is optionally provided as a liquid formulation in a ready to use stick pack.

DISCUSSION OF EMBODIMENTS

In various embodiments the therapeutically effective amount comprises about 50 mg of diclofenac or a pharmaceutically acceptable salt thereof. In other embodiments therapeutically effective amount comprises about 50 mg of diclofenac or a pharmaceutically acceptable salt thereof in from about 8 to about 25 or 50 g of said formulation. In other embodiments the therapeutically effective amount comprises about 50 mg of diclofenac or a pharmaceutically acceptable salt thereof in from about 8 to about 15 g or from about 15 to about 50 g or from about 15 to about 22 g of said formulation. In still other embodiments the therapeutically effective amount comprises about 50 mg of diclofenac or a pharmaceutically acceptable salt thereof in about 20 g of said formulation. The preferred salt of diclofenac in all embodiments is diclofenac potassium.

The formulation, and particularly the sugar-based aqueous means, can be defined in various terms. Thus, in one embodiment the sugar-based aqueous means comprises a sugar selected from the group consisting of mono-, di-, tri-, and tetra-saccharides and sugar alcohols and combinations thereof. In another embodiment the sugar-based aqueous means is selected from the group consisting of monosaccharides, sugar alcohols, water and combinations thereof the monosaccharides are selected from the group consisting of glucose, fructose, and galactose; and the sugar alcohols are selected from the group consisting of ethylene and or propylene glycol; glycerol; erythritol; threitol; arabitol; xylitol; ribitol; mannitol; sorbitol; galactitol; fucitol; iditol; inositol; volemitol; isomalt; maltitol; lactitol; maltotriitol; maltotetraitol; and polyglycitol. In another embodiment the sugar-based aqueous means comprises a sugar selected from monosaccharides and sugar alcohols and combinations thereof the monosaccharides are selected from the group consisting fructose; and the sugar alcohols are selected from the group consisting of glycerol; erythritol; xylitol; sorbitol; and maltitol.

The formulations can be provided in stick packs as a liquid or a solid powder or granule that is subsequently reconstituted in water prior to administration. Thus, the sugar-based aqueous means can be a liquid, or it can refer to a solid which is compatible with water when subsequently reconstituted. When a liquid stick pack is intended, the “sugar-based aqueous means” will be preceded by “liquid.”

The relative percentages of water and sugar in sugar-based aqueous means can vary, although it is generally preferable to have higher percentages of sugar. Thus, in some embodiments the sugar-based aqueous means comprises: from about 0% or 5% to about 95% water and from about 5% to about 95% of a sugar. In another embodiment the sugar-based aqueous means comprises from about 0% or 10% to about 60% water and from about 40% to about 90% of a sugar. In another embodiment the sugar-based aqueous means comprises from about 0% or 20% to about 40% water and from about 60% to about 80% of a sugar. In another embodiment the sugar-based aqueous means comprises: from 0% or 5% to about 95% water; and from about 5% to about 95% of a fruit sugar or monosaccharide or a combination thereof. In another embodiment the sugar-based aqueous means comprises: from about 0% or 10% to about 60% water; and from about 40% to about 90% of a fruit sugar or monosaccharide or a combination thereof. In another embodiment the sugar-based aqueous means comprises: from about 0% or 20% to about 40% water; and from about 60% to about 80% of a fruit sugar or monosaccharide or a combination thereof.

In another embodiment the sugar-based aqueous means comprises: from about 0% or 5% to about 95% water; and from about 5% to about 95% of a fruit sugar or monosaccharide or a combination thereof comprising: from about 10% to about 90% sorbitol; and from about 10% to about 90% of xylitol, maltitol, glycerol, fructose, erythritol or a combination thereof. In another embodiment the sugar-based aqueous means comprises: from about 0% or 10% to about 60% water; and from about 40% to about 90% of a fruit sugar or monosaccharide or a combination thereof comprising: from about 10% to about 90% sorbitol; and from about 10% to about 90% of xylitol, maltitol, glycerol, fructose, erythritol or a combination thereof. In another embodiment the sugar-based aqueous means comprises: from about 0% or 20% to about 40% water; and from about 60% to about 80% of a fruit sugar or monosaccharide or a combination thereof comprising: from about 10% to about 90% sorbitol; and from about 10% to about 90% of xylitol, maltitol, glycerol, fructose, erythritol or a combination thereof.

In another embodiment the sugar-based aqueous means comprises: from about 0% or 5% to about 95% water; and from about 5% to about 95% of sorbitol. In another embodiment the sugar-based aqueous means comprises: from about 0% or 10% to about 60% water; and from about 40% to about 90% of sorbitol. In another embodiment the sugar-based aqueous means comprises: from about 0% or 20% to about 40% water; and from about 60% to about 80% of sorbitol.

In another embodiment the sugar-based aqueous means comprises: from about 0% or 25% to about 75% water; and from about 25% to about 75% of xylitol. In another embodiment the sugar-based aqueous means comprises: from about 0% or 25% to about 75% water; and from about 25% to about 75% of maltitol. In another embodiment the sugar-based aqueous means comprises: from about 0% or 25% to about 75% water; and from about 25% to about 75% of glycerol. In another embodiment the sugar-based aqueous means comprises: from about 0% or 25% to about 75% water; and from about 25% to about 75% of fructose. In another embodiment the sugar-based aqueous means comprises: from about 0% or 55% to about 85% water; and from about 15% to about 45% of erythritol.

In some embodiments, a single sugar alcohol is included in the formulation selected from xylitol, maltitol, glycerin, erythritol, sorbitol, and non-crystallizing sorbitol. In other embodiments a combination of two sugar alcohols is included in the formulation selected from xylitol+sorbitol, xylitol+non-crystallizing sorbitol, maltitol+sorbitol, and maltitol+non-crystallizing sorbitol. When two sugar alcohols are present in combination, they are preferably present in a ratio of from about 10:90 to about 90:10.

In another embodiment the formulation comprises less than about 95% glycerol. In another embodiment the formulation is either substantially free of glycerol or completely free of glycerol. In another embodiment the formulation comprises less than about 15% ethanol. In another embodiment the formulation comprises less than about 2% ethanol. In still another embodiment the formulation is either substantially free of ethanol or completely free of ethanol.

Although bicarbonates ate preferred alkalizing agents, it will be understood that the formulations can contain any alkalizing agent, capable of producing the desired pH (preferably about 7.5 to about 10.0, or about 8.0 to about 9.0). Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, and trolamine and others known to those of ordinary skill in the art.

When a bicarbonate is used as the alkalizing agent, the formulations can also be defined more particularly in terms of the diclofenac and bicarbonate content of the formulation. Thus, in another embodiment the formulation comprises from about 0.1% to about 1% diclofenac or a pharmaceutically acceptable salt thereof; from about 0.05% to about 1.5% bicarbonate; and from 9 about 5% to about 99.85% of said sugar-based aqueous means. Once again, the diclofenac is preferably present as diclofenac potassium and the bicarbonate present as potassium bicarbonate.

In still another embodiment the formulation comprises from about 0.1% to about 1% diclofenac or a pharmaceutically acceptable salt thereof; from about 0.05% to about 1% bicarbonate or from about 0.1 to about 2% bicarbonate; and from about 95% to about 99.85% of said sugar-based aqueous means. Once again, the diclofenac is preferably present as diclofenac potassium and the bicarbonate present as potassium bicarbonate.

In another embodiment the formulation comprises additional ingredients selected from the group consisting of thickeners and sweeteners and taste modifying agents. In another embodiment the formulation comprises additional ingredients selected from the group consisting of sucralose, polyvinylpyrrolidone and hydroxyethylcellulose. Suitable taste-masking agents include cellulose hydroxypropyl ethers (HPC); low-substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC); methylcellulose polymers; Ethylcelluloses (EC) and mixtures thereof; Polyvinyl alcohol (PVA); hydroxyethylcelluloses; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC); polyvinyl alcohol and polyethylene glycol co-polymers; monoglycerides, triglycerides, polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers; cellulose acetate phthalate; sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures thereof.

Suitable flavoring agents include acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate, maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, neotame, acesulfame potassium, mannitol, talin, xylitol, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, and mixtures thereof.

In another embodiment the formulation of the present invention has a density of from about 1.02 to about 1.5 g/ml. In another embodiment the formulation of the present invention has a density of from about 1.05 to about 1.35 g/ml. In still another embodiment the formulation of the present invention has a density of from about 1.1 to about 1.25 g/ml.

The materials used to construct the laminate sheet for the stick pack can be any that are customary in the art, such as polyester, polypropylene, polyethylene and polyethylene terephthalate (PET), provided that the stick pack is sufficiently tear resistant until correctly manipulated. In preferred embodiments the laminate comprises a layer of aluminum foil. Examples of suitable designs for stick packs are described, for example in US 2015/0144518A1 and US20030168375A1. Suitable stick packs can also be purchased from companies such as Unette Corporation (Randolph N.J.) and Amcor 360 Packaging Solutions (Melbourne Australia).

In another embodiment the formulation is present in a stick pack comprising a trilaminate of polyester, aluminum and polyethylene. In another embodiment the formulation is present in a stick pack comprising a trilaminate of polyester, aluminum and polyethylene, wherein said trilaminate: (a) has a layer thickness of 12/8.5/65 μm, respectively; (a) has a weight of 16.8/22.9/59.9 g/mq, respectively; (c) has micropores in the aluminum layer less than 300/mq.

In still other embodiments the formulation of the present invention has a pH of from about 7.5 to about 10.0. In another embodiment the formulation of the present invention has a pH of from about 8.0 to about 9.0.

In another embodiment the formulation of the present invention comprises less than about 1% total impurities. In another embodiment the formulation of the present invention has less than about 1% total impurities after storage at 40° C.±2° C. and 75% RH ±5% RH for three or six months.

In another embodiment the diclofenac is present in the formulation as diclofenac potassium and the bicarbonate is present as potassium bicarbonate. In another embodiment the diclofenac is present in the formulation as diclofenac potassium and said bicarbonate is present as potassium bicarbonate at a weight ratio of from about 50:10 to about 50:100, about 50:10 to about 50:50, or about 50:50 to about 50:100, preferably about 50:22 or about 50:66.

In certain embodiments, the sugar-based aqueous means comprises sorbitol, and the sorbitol is either a crystallizing sorbitol solution or a non-crystallizing sorbitol solution, or a combination of both, as those terms are understood in the art and described in the United States Pharmacopoeia in effect on Dec. 1, 2019. In one particular embodiment the formulation comprises between 25% and 90% of a non-crystallizing sorbitol solution. In one particular embodiment the liquid formulation of the present invention comprise a sugar-based aqueous means contains both non-crystallizing sorbitol solution and crystallizing sorbitol solution.

In another embodiment the liquid formulation of the present invention comprises a sugar-based aqueous containing an antimicrobial agent.

In any of the embodiments and embodiments of the present invention, it will be understood that the formulation can be present as a liquid, and that the liquid will predominantly be water. Thus, in any of the embodiments and embodiments of this invention the formulation can be present as a liquid and the sugar based aqueous means comprise greater than about 5%, about 10%, or about 20% water. Alternatively, in any of the embodiments and embodiments of the invention the formulation can be present as a liquid, and the sugar based aqueous means comprise from about 5% to about 50% water or from about 10% to about 40% water. Alternatively, in any of the embodiments and embodiments of the invention the formulation can be present as a liquid comprising greater than about 5%, about 10%, or about 20% water. Alternatively, in any of the embodiments and embodiments of the invention the formulation is present as a liquid comprising from about 5% to about 50% water or from about 10% to about 40% water.

EXAMPLES

In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods claimed herein are made and evaluated and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.

All the formulations/prototypes described herein have been tested for all or some of the following parameters: (1) Taste/Smell/Texture; (2) pH (3) Appearance; and (4) Assay and Impurities. Impurities were analyzed using two separate methods.

Assay and Impurity Method A (Impurities 1, 2, 3, 4, 6) ANALYTICAL EQUIPMENT: HPLC

ANALYTICAL COLUMN: ALLTIMA C18 5 μm 250×4.6 mm or equivalent MOBILE PHASE: 72.5% Methanol 27.5% buffer potassium dihydrogen phosphate (KH2PO4) 0.01M; Correct the mobile phase to pH 3.75±0.10 with phosphoric acid FLOW RATE: 1.3 mL/min

WAVELENGTH: 256 nm INJECTED VOLUME: 20 μL TEMPERATURE: 30° C.

ACQUISITION LENGTH: 25 minutes

SOLVENT: Methanol Related Substance Retention Time:

IMPURITY A (3): about 6.5 min IMPURITY B (6): about 15.0 min IMPURITY C (4): about 9.0 min IMPURITY 1: about 3.5 min IMPURITY 2: about 4.5 min DICLOFENAC K RETENTION TIME: about 11.0 minutes

Impurity Profile (Impurity 5) Method B ANALYTICAL EQUIPMENT: HPLC

ANALYTIC COLUMN: ALLTIMA C18 5 μm 250×4.6 mm or equivalent MOBILE PHASE: 60.0% Acetonitrile; 39.5% Water; 0.4% Phosphoric Acid; 0.1% Triethylamine; correct the mobile phase to pH 5.00±0.20 with Sodium Hydroxide 1N FLOW RATE: 1.2 mL/min

WAVELENGTH: 256 nm INJECTED VOLUME: 20 μL TEMPERATURE COLUMN: 25° C.

ACQUISITION LENGTH: 25 minutes IMPURITY 5: about 9.0 min DICLOFENAC K RETENTION TIME: about 8.0 minutes

Total Impurities

CALCULATE THE AMOUNT OF TOTAL IMPURITIES % by the formula: Impurities total %: Σ Impurities total % (Method A)+ΣImpurities total % (Method B);

Notes

-   -   The reporting threshold for impurities is 0.1%, according to ICH         Q3B_R2;     -   The related substances retention times are indicative and         referred to the main peak.

Stability Studies

All the formulations/prototypes manufactured and here below described have been stored under the following storage conditions:

Storage conditions 25° C. ± 2° C./60% RH ± 5%    Long Term conditions 30° C. ± 2° C./75% RH ± 5% RH Intermediate conditions 40° C. ± 2° C./75% RH ± 5% RH Accelerated conditions 5° C. Back up conditions

Primary Packaging

The following primary packaging has been evaluated for R&D stability purposes:

-   -   Amber Glass Vial 15 ml (filled with 8 ml of formula, leaving         headspace of about 7 ml);     -   Stick packs used for stability testing were made of a         Polyester/Aluminum/Polythene tri-layer laminate characterized by         the following properties:         -   thickness 12/8.5/65μ         -   weight 16.8/22.9/59.9 g/mq         -   micropores for the Aluminum layer<300/mq

Sorbitol

The Non crystallizing Sorbitol Solution used in the following Examples is the Neosorb 70/70B® (Roquette) that complies with the USP-NF specifications related to non-crystallizing sorbitol solution. The characteristics of Neosorb 70/70B are as follows:

-   -   Anhydrous substance: 68,0-72,0%     -   Water: 28-32%     -   D-glucitol (D-sorbitol): 72,0-92,0% (Anhydrous substance)

The crystallizing sorbitol solution used in the following Examples is the Emprove® Essential (Merk) that complies with the USP-NF specifications related to crystallizing sorbitol solution. The characteristics of Emprove® Essential are as follows:

-   -   Anhydrous substance: 69,0-72,0%     -   Water: 28.5-31%     -   D-glucitol (D-sorbitol): 92,0-101,0% (Anhydrous substance)

Example 1 Liquid Oral Solution with Diclofenac and High Quantity of Sorbitol (Prototype PFS DK 27-bkT038/72)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50.0 0.25 2.5 2 Potassium Bicarbonate 22.0 0.11 1.1 (KHCO3) 3 Non crystallizing 19928.0 99.64 996.4 Sorbitol Solution Total 20000 100 1000.0

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution in a glass container; treat the solution with nitrogen         flow for about 30 minutes;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring and under         nitrogen flow;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring and under nitrogen flow for all the         time;     -   Filter the solution;     -   Store the solution in the selected container;     -   Treat the headspace of the container with nitrogen flow before         close the container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK27 - bkT038/72 specifications Time zero Vials Stick Pack Appearance of the solution Colourless Complies Slightly Pale clear yellow yellow solution clear clear solution solution pH (on sample, as it is) To be defined 8.44  8.45 8.22 Diclofenac K Assay (%) 95.0-105.0 98.8   97.5  97.1  Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 0.105 — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — Total (known and NMT 1.0 0.105 — — unknown) impurities (%)

Example 2 Liquid Oral Solution with Diclofenac and Medium Quantity of Sorbitol (Prototype PFS DK 33-bkT038/87)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; a reduced concentration of sorbitol in comparison to Example 1 is tested.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.250 2.5 2 Potassium Bicarbonate 22 0.110 1.1 (KHCO3) 3 Non crystallizing 14286 71.43 714.3 Sorbitol Solution 4 Water 5642 28.21 282.1 Total 20000 100.00 1000

Manufacturing Method

-   -   Transfer the total quantity of water and Non crystallizing         Sorbitol Solution in a glass container; treat the solution with         nitrogen flow for about 30 minutes;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring and under         nitrogen flow;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring and under nitrogen flow for all the         time;     -   Filter the solution;     -   Store the solution in the selected container;     -   Treat the headspace of the container with nitrogen flow before         close the container.

Analytical Evaluations

Stability data Time 6 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 33 - bkT038/87 specifications Time zero Vials Stick Pack Appearance of the solution Colourless Complies Yellow Yellow clear clear clear solution solution solution pH (on sample, as it is) To be defined 8.57 8.02  8.31  Diclofenac K Assay (%) 95.0-105.0 103.8 97.9   95.8   Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — 0.252 0.263 UNK 15 (%) RRT = 0.550 NMT 0.2 — 0.290 — Total (known and unknown) NMT 1.0 — 0.542 0.263 impurities (%)

Example 3 Liquid Oral Solution with Diclofenac and Low Quantity of Sorbitol (Prototype PFS DK 32-bkT038/86)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; a reduced concentration of sorbitol in comparison to Examples 1 and 2 has been tested.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.25 2.5 2 Potassium Bicarbonate 22 0.11 1.1 (KHCO3) 3 Non crystallizing 7122 35.6 356.1 Sorbitol Solution 4 Water 12806 64.0 640.3 Total 20000 100.0 1000.0

Manufacturing Method

-   -   Transfer the total quantity of water and Non crystallizing         Sorbitol Solution in a glass container; treat the solution with         nitrogen flow for about 30 minutes;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring and under         nitrogen flow;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring and under nitrogen flow for all the         time;     -   Filter the solution;     -   Store the solution in the selected container;     -   Treat the headspace of the container with nitrogen flow before         close the container.

Analytical Evaluations

Stability data Time 3 months Time 3 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 32 - bkT038/86 specifications Time zero Vials Stick Pack Appearance of the solution Colourless Complies Pale yellow Complies clear clear solution solution pH (on sample, as it is) To be defined 8.63 8.56  8.31 Diclofenac K Assay (%) 95.0-105.0 102.9 97.6   97.7 Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — 0.115 0.115 Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — 0.133 — IMPURITY 15 (%) NMT 0.2 — 0.255 — RRT = 0.550 Total (known and unknown) NMT 1.0 — 0.503 0.115 impurities (%) Note: The 6 months analyses were not performed due to the presence of mold in the samples

Example 4 Liquid Oral Solution with Diclofenac without Sorbitol (Prototype PFS DK 31-bkT038/85)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; the sorbitol syrup used for Examples 1, 2 and 3 is replaced with water.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50.0 0.25 2.50 2 Potassium Bicarbonate 22.0 0.11 1.10 (KHCO3) 3 Water 19928.0 99.64 996.40 Total 20000 100.0 1000.0

Manufacturing Method

-   -   Transfer the total quantity of water in a glass container; treat         the solution with nitrogen flow for about 30 minutes;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring and under         nitrogen flow;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring and under nitrogen flow for all the         time;     -   Filter the solution;     -   Store the solution in the selected container;     -   Treat the headspace of the container with nitrogen flow before         close the container.

Analytical evaluations

Stability data Time 3 months Time 6 months Time 4 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH 40° C., 75% RH 40° C., 75% RH PFS DK 31 - bkT038/85 specifications Time zero Vials Vials Stick Pack Stick Pack Appearance of the solution Colourless Complies Complies Yellow Complies Yellow clear clear clear solution solution solution pH (on sample, as it is) To be defined 9.00  9.24  9.30  8.94  9.10  Diclofenac K Assay (%) 95.0-105.0 103.8   97.7   97.1   97.7   96.0   Impurity 1 (%) RRT = 0.38 NMT 0.2 — 0.608 1.029 — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — 0.293 — 0.183 0.333 Impurity C (4) (%) RRT = 0.82 NMT 0.2 0.101 0.249 0.242 0.282 0.238 Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — 0.589 — 0.500 Total (known and unknown) NMT 1.0 0.101 1.150 1.860 0.465 1.071 impurities (%)

Example 5 Liquid Oral Solution with Diclofenac and High Quantity of Sorbitol, without Nitrogen (Prototype PFS DK 34-bkT038/88)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula. Differently from Example 1, the preparation has not been carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50.0 0.25 2.50 2 Potassium Bicarbonate 22.0 0.11 1.10 (KHCO3) 3 Non crystallizing 19928.0 99.64 996.40 Sorbitol Solution Total 20000 100 1000.0

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 34 - bkT038/88 specifications Time zero Vials Stick Pack Appearance of the solution Colourless Complies Slightly Slightly clear yellow yellow solution clear clear solution solution pH (on sample, as it is) To be defined 8.19 8.38 8.01  Diclofenac K Assay (%) 95.0-105.0 101.9 97.8  95.6   Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — 0.154 Total (known and unknown) NMT 1.0 — — 0.154 impurities (%) The Time 6 months analyses have been performed only on stick packs

Example 6 Liquid Oral Solution with Diclofenac and Medium Quantity of Sorbitol, without Nitrogen (Prototype PFS DK 42-bkT038/117)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula. Differently from Example 2, the preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.250 2.5 2 Potassium Bicarbonate 22 0.110 1.1 (KHCO3) 3 Non crystallizing 14286 71.43 714.3 Sorbitol Solution 4 Water 5642 28.21 282.1 Total 20000 100.00 1000

Manufacturing Method

-   -   Transfer the total quantity of water and Non crystallizing         Sorbitol Solution in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 42 - bkT038/117 specifications Time zero Vials Vials Appearance of the solution Colourless Complies Slightly yellow Slightly yellow clear solution with solution with solution mold floccules reticulated mold pH (on sample, as it is) To be defined n.d. 8.59 8.57 Diclofenac K Assay (%) 95.0-105.0 99.1 Not performed Not performed Impurity 1 (%) RRT = 0.38 NMT 0.2 — Impurity 2 (%) RRT = 0.44 NMT 0.2 — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — Impurity 5 (%) RRT = 1.12 NMT 0.2 — Total (known and unknown) NMT 1.0 — impurities (%)

Note: HPLC analyses have not been performed on samples that showed mold formation

Example 7 Liquid Oral Solution with Diclofenac and Low Quantity of Sorbitol, without Nitrogen (Prototype PFS DK 41-bkT038/116)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula. Differently from Example 3, the preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.25 2.5 2 Potassium Bicarbonate 22 0.11 1.1 (KHCO3) 3 Non crystallizing 7122 35.6 356.1 Sorbitol Solution 4 Water 12806 64.0 640.3 Total 20000 100.00 1000

Manufacturing Method

-   -   Transfer the total quantity of water and Non crystallizing         Sorbitol Solution in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 41 - bkT038/116 specifications Time zero Vials Vials Appearance of the solution Colourless Complies Slightly Slightly yellow clear yellow clear solution with solution solution reticulated mold pH (on sample, as it is) To be n.d. 8.75 8.73 defined Diclofenac K Assay (%) 95.0-105.0 100.5 99.7  Not performed Impurity 1 (%) RRT = 0.38 NMT 0.2 — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — Total (known and unknown) NMT 1.0 — — impurities (%) Note: HPLC analyses have not been performed on samples that showed mold formation

Example 8 Liquid Oral Solution with Diclofenac without Sorbitol (Prototype PFS DK 40-bkT038/115), without Nitrogen

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula, using water as solvent. Differently from Example 4, the preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick % g/bulk (1000 g) 1 Diclofenac K 50.0 0.25 2.50 2 Potassium Bicarbonate 22.0 0.11 1.10 (KHCO3) 3 Water 19928.0 99.64 996.40 Total 20000 100.0 1000.0

Manufacturing Method

-   -   Transfer the total quantity of water in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 40 - bkT038/115 specifications Time zero Vials Vials Appearance of the solution Colourless Complies Complies Slightly clear yellow solution clear solution pH (on sample, as it is) To be defined n.d. 9.27  9.28  Diclofenac K Assay (%) 95.0-105.0 100.7   100.0   99.9   Impurity 1 (%) RRT = 0.38 NMT 0.2 — 0.445 1.608 Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — 0.327 0.245 Impurity C (4) (%) RRT = 0.82 NMT 0.2 0.138 0.191 0.155 Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — 0.376 Total (known and unknown) NMT 1.0 0.138 0.963 2.384 impurities (%)

Example 9 Liquid Oral Solution with Diclofenac and Xylitol, with and without Nitrogen (Prototype PFS DK 46-bkT038/122 and Prototype PFS DK 43-bkT038/118)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; the sorbitol used in the previous examples is replaced with Xylitol in both the prototypes that have the same quali/quantitative formula but differ for the use of nitrogen during the manufacturing.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (2000 g) 1 Diclofenac K 50 0.250 5.000 2 Potassium Bicarbonate 22 0.110 2.200 (KHCO3) 3 Xylitol 10000 50.0 1000.0 4 Water 9928 49.6 992.8 Total 20000 100.00 2000

Manufacturing Method

PFS DK 46-bkT038/122

-   -   Transfer the total quantity of water and Xylitol in a glass         container; treat the solution with nitrogen flow for about 30         minutes and wait for the complete dissolution;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring and under         nitrogen flow;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring and under nitrogen flow for all the         time;     -   Filter the solution;     -   Store the solution in the selected container;     -   Treat the headspace of the container with nitrogen flow before         close the container.

PFS DK 43-BkT038/118

-   -   Transfer the total quantity of water and Xylitol in a glass         container and wait for the complete dissolution;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 25° C., 60% RH 40° C., 75% RH PFS DK 46 - bkT038/122 specifications Time zero Vials Stick Pack Appearance of the solution Colourless Complies Complies Yellow clear clear solution solution pH (on sample, as it is) To be defined 8.42 8.93 7.34 Diclofenac K Assay (%) 95.0-105.0 100.4 100.3 95.7  Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — Total (known and unknown) NMT 1.0 — — — impurities (%) Time 3 months Time 6 months Tentative 25° C., 60% RH 40° C., 75% RH PFS DK 43 - bkT038/118 specifications Time zero Vials Stick Pack Appearance of the solution Colourless Complies Complies Pale clear yellow solution clear solution pH (on sample, as it is) To be defined 8.59 7.96 7.89  Diclofenac K Assay (%) 95.0-105.0 98.3  96.2  95.2   Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — 0.133 Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — Total (known and unknown) NMT 1.0 — — 0.133 impurities (%)

Example 10 Liquid Oral Solution with Diclofenac, Maltitol and Sucralose, without Nitrogen (Prototype PFS DK 89-bkT038/174)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; maltitol and sucralose are here mixed with water to obtain the formula. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.250 2.5 2 Potassium Bicarbonate 22 0.110 1.10 (KHCO3) 3 Maltitol syrup 75% 13333 66.7 666.65 4 Water 6583 32.9 329.15 5 Sucralose 12 0.0600 0.60 Total 20000 100.00 1000

Manufacturing Method

-   -   Transfer the total quantity of Maltitol syrup and water in a         glass container;     -   Add Sucralose and Potassium Bicarbonate and wait for the         complete dissolution (about 5 minutes); maintain the system         under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 89 - bkT038/174 specifications Time zero Vials Vials Appearance of the solution Colourless Complies Slightly Slightly clear yellow orange solution clear clear solution solution pH (on sample, as it is) To be defined 8.43 8.58 8.39  Diclofenac K Assay (%) 95.0-105.0 100.3 101.2 98.3   Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — 0.243 Total (known and unknown) NMT 1.0 — — 0.243 impurities (%)

Example 11 Liquid Oral Solution with Diclofenac and Glycerin, without Nitrogen (Prototype PFS DK 88-bkT038/173)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; glycerin is here used to obtain the formula. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.250 2.50 2 Potassium Bicarbonate 22 0.110 1.10 (KHCO3) 3 Glycerin 10000.00 50.0 500.00 4 Water added to 100% 9916 49.6 495.80 5 Sucralose 12 0.0600 0.60 Total 20000 100.00 1000.00

Manufacturing Method

-   -   Transfer the total quantity of glycerin and water in a glass         container;     -   Add Sucralose and Potassium Bicarbonate and wait for the         complete dissolution (about 5 minutes); maintain the system         under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 88 - bkT038/173 specifications Time zero Vials Vials Appearance of the solution Colourless Complies Complies Pale clear yellow solution clear solution pH (on sample, as it is) To be defined 8.25 8.86  8.97  Diclofenac K Assay (%) 95.0-105.0 100.1 100.8   97.3   Impurity 1 (%) RRT = 0.38 NMT 0.2 — 0.109 0.176 Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — 0.126 0.117 Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — Total (known and NMT 1.0 — 0.235 0.293 unknown) impurities (%)

Example 12 Liquid Oral Solution with Diclofenac and Erythritol without Nitrogen (Prototype PFS DK 90-bkT038/175)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; erythritol is here used to obtain the formula. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (500 g) 1 Diclofenac K 50 0.25 1.25 2 Potassium Bicarbonate 22 0.11 0.55 (KHCO3) 3 Erythritol 6000 30 150 4 Water 13916 69.58 347.9 5 Sucralose 12 0.06 0.3 Total 20000 100.00 500.00

Manufacturing Method

-   -   Transfer the total quantity of water in a glass container;     -   Add Erythritol, Sucralose and Potassium Bicarbonate and wait for         the complete dissolution; maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 90 - bkT038/175 specifications Time zero Vials Vials Appearance of the solution Colourless Complies Slightly Slightly clear yellow yellow solution clear clear solution solution pH (on sample, as it is) To be defined 8.68 7.31 7.02 Diclofenac K Assay (%) 95.0-105.0 100.5 99.3  95.4  Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — Total (known and unknown) NMT 1.0 — — — impurities (%)

Example 13 Liquid Oral Solution with Diclofenac and Fructose, without Nitrogen (Prototype PFS DK 95-bkT038/186)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; water and fructose are here mixed to obtain the formula. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (500 g) 1 Diclofenac K 50 0.25 1.25 2 Potassium Bicarbonate 22 0.11 0.55 (KHCO3) 3 Fructose 10000 50.00 250.00 4 Water 9916 49.58 247.90 5 Sucralose 12 0.06 0.300 Total 20000 100.00 500.00

Manufacturing Method

-   -   Transfer the total quantity of water in a glass container and         dissolve the Fructose;     -   Add Diclofenac K, sucralose and Potassium Bicarbonate and stir         until complete dissolution;     -   Filter the solution;     -   Store the solution in the selected container.

Example 14 Liquid Oral Solution with Diclofenac and Non Crystallizing Sorbitol Solution—10 ml Volume (Prototype PFS DK 47-bkT038/123)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in, differently from Example 1, 12.5 g of formula. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50.0 0.40 4.0 2 Potassium Bicarbonate 22.0 0.18 1.8 (KHCO3) 3 Non crystallizing 12428.0 99.42 994.2 Sorbitol Solution Total 12500 100.00 1000.0

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 47 - bkT038/123 specifications Time zero Vials Vials Appearance of the solution Colourless Complies Pale Orange clear yellow clear solution clear solution solution pH (on sample, as it is) To be defined — 8.43 8.45  Diclofenac K Assay (%) 95.0-105.0 100.1   100.1 100.2   Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — 0.150 Impurity C (4) (%) RRT = 0.82 NMT 0.2 0.138 — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — Total (known and unknown) NMT 1.0 0.138 — 0.150 impurities (%)

Example 15 Liquid Oral Solution with Diclofenac, Sorbitol and Xylitol, with and without Nitrogen (Prototype PFS DK 49-bkT038/126 and Prototype PFS DK 44-bkT038/119)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; sorbitol and xylitol are here mixed for both the prototypes that have the same quali/quantitative formula but differ for the use of nitrogen during the manufacturing.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (2000 g) 1 Diclofenac K 50 0.250 5.000 2 Potassium Bicarbonate 22 0.110 2.200 (KHCO3) 3 Non crystallizing 7142.8 35.7 714.3 Sorbitol Solution 4 Xylitol 5000 25.0 500.0 5 Water added to 100% 7785.2 38.9 778.5 Total 20000 100.00 2000

Manufacturing Method PFS DK 49-BkT038/126

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, Xylitol and water in a glass container; treat the         solution with nitrogen flow for about 30 minutes;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring and under         nitrogen flow;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring and under nitrogen flow for all the         time;     -   Filter the solution;     -   Store the solution in the selected container;     -   Treat the headspace of the container with nitrogen flow before         close the container.         PFS DK 44-bkT038/119     -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, Xylitol and water in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability Data Time 3 months Time 3 months Tentative 25° C., 60% RH 40° C., 75% RH PFS DK 49 - bkT038/126 specifications Time zero Vials Vials Appearance of the solution Colourless Complies Complies Slightly clear yellow solution clear solution pH (on sample, as it is) To be defined 8.48  8.77  8.75  Diclofenac K Assay (%) 95.0-105.0 100.2   98.6   97.6   Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 0.100 0.189 0.189 Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — 0.145 UNK 4 (%) RRT = 0.578 NMT 0.2 — — 0.136 Total (known and unknown) NMT 1.0 0.100 0.189 0.470 impurities (%)

Example 16 Liquid Oral Solution with Diclofenac, Sorbitol and Xylitol, with and without Nitrogen (Prototype PFS DK 48-bkT038/125 and Prototype PFS DK 45-bkT038/121)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; sorbitol and xylitol are here mixed for both the prototypes that have the same quali/quantitative formula but differ for the use of nitrogen during the manufacturing.

Ingredient mg/stick pack % g/bulk (2000 g) 1 Diclofenac K 50 0.250 5.000 2 Potassium Bicarbonate 22 0.110 2.200 (KHCO3) 3 Non crystallizing 14285.7 71.4 1428.6 Sorbitol Solution 4 Xylitol 4000 20.0 400.0 5 Water added to 100% 1642.3 8.2 164.2 Total 20000 100.0 2000

Manufacturing Method

PFS DK 48-bkT038/125

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, Xylitol and water in a glass container; treat the         solution with nitrogen flow for about 30 minutes;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring and under         nitrogen flow;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring and under nitrogen flow for all the         time;     -   Filter the solution;     -   Store the solution in the selected container;     -   Treat the headspace of the container with nitrogen flow before         close the container.         PFS DK 45-bkT038/121     -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, Xylitol and water in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 3 months Tentative 25° C., 60% RH 40° C., 75% RH PFS DK 48 - bkT038/125 specifications Time zero Vials Vials Appearance of the solution Colourless Complies Complies Slightly clear yellow solution clear solution pH (on sample, as it is) To be defined 8.57 8.76 8.77  Diclofenac K Assay (%) 95.0-105.0 101.4   100.2   102.1   Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — 0.104 Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — Total (known and unknown) NMT 1.0 — — 0.104 impurities (%) Time 3 months Time 3 months Tentative 25° C., 60% RH 40° C., 75% RH PFS DK 45 - bkT038/121 specifications Time zero Vials Vials Appearance of the solution Colourless Complies Complies Slightly clear yellow solution clear solution pH (on sample, as it is) To be defined 8.49  8.70  8.61  Diclofenac K Assay (%) 95.0-105.0 101.1   101.0   99.6   Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 0.150 0.185 0.163 Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — 0.101 Total (known and unknown) NMT 1.0 0.150 0.185 0.264 impurities (%)

Example 17 Liquid Oral Solution with Diclofenac and High Quantity of Sorbitol, with Sucralose (Prototype PFS DK 26A-bkT038/71)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula. Differently from Example 1, Sucralose is added to Non crystallizing Sorbitol Solution; the preparation is carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (500 g) 1 Diclofenac K 50 0.25 1.25 2 Potassium Bicarbonate 22 0.11 0.55 (KHCO3) 3 Sucralose 12 0.06 0.30 4 Non crystallizing 19916 99.58 497.90 Sorbitol Solution Total 20000 100 500.0

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution in a glass container; treat the solution with nitrogen         flow for about 30 minutes;     -   Add Sucralose and Potassium Bicarbonate and wait for the         complete dissolution (about 5 minutes); maintain the system         under stirring and under nitrogen flow;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring and under nitrogen flow for all the         time;     -   Filter the solution;     -   Store the solution in the selected container;     -   Treat the headspace of the container with nitrogen flow before         close the container.

Analytical Evaluations

Stability data Time 3 months Time 6 months Tentative 40° C., 75% RH 40° C., 75% RH PFS DK 26A - bkT038/71 specifications Time zero Stick Pack Stick Pack Appearance of the solution Colourless Complies Pale Pale clear yellow yellow solution clear clear solution solution pH (on sample, as it is) To be defined 8.46 7.91 7.92 Diclofenac K Assay (%) 95.0-105.0 99.7  100.5 96.1  Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — Total (known and unknown) NMT 1.0 — — — impurities (%)

Example 18 Liquid Oral Solution with Diclofenac and High Quantity of Sorbitol, with Sucralose—14 ml Volume (Prototype PFS DK 70-bkT038/149)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in, differently from Example 13, in 18.2 g of formula. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.275 2.75 2 Potassium Bicarbonate 22 0.121 1.21 (KHCO3) 3 Sucralose 6.0 0.033 0.33 4 Non crystallizing 18122 99.57 995.7 Sorbitol Solution Total 18200.0 100.0 1000.0

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution in a glass container;     -   Add Sucralose and Potassium Bicarbonate and wait for the         complete dissolution (about 5 minutes); maintain the system         under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 3 months Time 3 months Tentative 25° C., 60% RH 30° C., 65% RH 40° C., 75% RH PFS DK 70 - bkT038/149 specifications Time zero Stick Pack Stick Pack Stick Pack Appearance of the solution Colourless Complies Complies Complies Slightly clear yellow solution clear solution pH (on sample, as it is) To be defined 8.60 8.33 8.32 8.12 Diclofenac K Assay (%) 95.0-105.0 98.7  100.9 100.9 100.2 Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 0.11 — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — — Total (known and unknown) NMT 1.0 0.11 — — — impurities (%)

Example 19 Liquid Oral Solution with Diclofenac and High Quantity of Sorbitol, without Sucralose—14 ml Volume (Prototype PFS DK 77-bkT038/156)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in, differently from Example 1, 18.2 g of formula. Differently from Example 14, the formula does not contain Sucralose. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.275 2.75 2 Potassium Bicarbonate 22 0.121 1.21 (KHCO3) 3 Non crystallizing 18128.0 99.6 996.04 Sorbitol Solution Total 18200.0 100.0 1000.0

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 6 months Tentative 40° C., 75% RH PFS DK 77 - bkT038/156 specifications Time zero Stick Pack Appearance of the solution Colourless Complies Slightly yellow clear clear solution with solution orange reflections pH (on sample, as it is) To be defined 8.53 8.01 Diclofenac K Assay (%) 95.0-105.0 99.3  99.0  Impurity 1 (%) RRT = 0.38 NMT 0.2 — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — Total (known and unknown) NMT 1.0 — — impurities (%)

Example 20 Liquid Oral Solution with Diclofenac and High Quantity of Sorbitol, with Polyvinylpyrrolidone—14 ml Volume, with and without Flavoring Agent (Prototype PFS DK 85-bkT038/168 and Prototype PFS DK 87-bkT038/170)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 18.2 g of formula. The addition of PVP, with and without a flavoring agent, is here evaluated. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

PFS DK 85- PFS DK 87- PFS DK 85- PFS DK 87- PFS DK 85- PFS DK 87- bkT038/168 bkT038/170 bkT038/168 bkT038/170 bkT038/168 bkT038/170 Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 50 0.275 0.275 2.747 2.747 2 Potassium Bicarbonate 22 22 0.121 0.121 1.209 1.209 (KHCO3) 3 Polyvinylpyrrolidone 80 80 0.4396 0.4396 4.396 4.396 (PVP) 4 Non crystallizing 18015.2 18048.0 99.0 99.2 989.846 991.648 Sorbitol Solution 5 Masking Bitter Flavor 32.8 — 0.18 — 1.802 — Total (mg) 18200.0 18200.0 100.0 100.0 1000.0 1000.0

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution in a glass container;     -   Add PVP and wait for the complete dissolution (about 5 minutes);         maintain the system under stirring;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Add the flavor (for PFS DK 85)     -   Store the solution in the selected container.

Analytical Evaluations

Stability data (performed only on PFS DK 87-bkT038/170) Time 12 months Time 6 months Time 6 months Tentative 25° C., 60% RH 30° C., 65% RH 40° C., 75% RH PFS DK 87 - bkT038/170 specifications Time zero Stick Pack Stick Pack Stick Pack Appearance of the solution Colourless Complies Complies Complies Pale yellow clear clear solution solution pH (on sample, as it is) To be defined 8.40 8.06 8.38 8.15 Diclofenac K Assay (%) 95.0-105.0 99.5  97.3  101.2 99.4 Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — 0.122 Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — — Total (known and unknown) NMT 1.0 — — — 0.122 impurities (%)

Example 21 Liquid Oral Solution with Diclofenac and Medium Quantity of Sorbitol, with Polyvinylpyrrolidone and Hydroxyethylcellulose—14 ml Volume, with Flavoring Agent (Prototype PFS DK 86-bkT038/169)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 18.2 g of formula. The addition of Hydroxyethylcellulose (HEC) and Polyvinylpyrrolidone (PVP), with a flavoring agent, is here evaluated. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (100 g) 1 Diclofenac K 50 0.275 2.755 2 Potassium Bicarbonate 22 0.121 1.212 (KHCO3) 3 Non crystallizing 14325 78.71 787.1 Sorbitol Solution 4 Water 3620 19.89 198.9 5 Polyvinylpyrrolidone 100 0.55 5.5 (PVP) 6 Hydroxyethyl 50 0.27 2.7 cellulose (HEC) 7 Masking Bitter Flavor 33 0.18 1.8 Total 18200.0 100.0 1000.0

Manufacturing Method

-   -   Dissolve under stirring all the PVP, add the HEC in water and         wait for the complete dissolution (about 3 hours);     -   Transfer the total quantity of Non crystallizing Sorbitol         Solution in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Mix the solutions obtained;     -   Add the flavor and mix for 5 minutes;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 3 months Time 3 months Tentative 25° C., 60% RH 30° C., 65% RH 40° C., 75% RH PFS DK 86 - bkT038/169 specifications Time zero Stick Pack Stick Pack Stick Pack Appearance of the solution Colourless Complies Complies Complies Dark yellow clear clear solution solution pH (on sample, as it is) To be defined 7.78 7.78 7.82 7.55 Diclofenac K Assay (%) 95.0-105.0 101.0 102.0 102.1 100.9 Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — 0.385 Total (known and unknown) NMT 1.0 — — — 0.385 impurities (%)

Example 22 Liquid Oral Solution with Diclofenac, Medium Quantity of Sorbitol, Erythritol and Sucralose, without Nitrogen (Prototype PFS DK 63-bkT038/140)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula; sorbitol and erythritol are here mixed with sucralose and water to obtain the formula. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (100 g) 1 Diclofenac K 50 0.25 0.25 2 Potassium Bicarbonate 22 0.11 0.11 (KHCO3) 3 Erythritol 5000 25.00 25.00 4 Non ctystallizing 7142 35.71 35.71 Sorbitol Solution 5 Water 7774 38.87 38.87 6 Sucralose 12 0.06 0.06 Total (mg) 20000 100 100

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, Erythritol and water in a glass container;     -   Add Sucralose and Potassium Bicarbonate and wait for the         complete dissolution (about 5 minutes); maintain the system         under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Example 23 Liquid Oral Solution with Diclofenac Sorbitol and Glycerin without Nitrogen (Prototype PFS DK 91-bkT038/176)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 16 g of formula; Sorbitol and Glycerin are here mixed to obtain the formula. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.31 3.13 2 Potassium Bicarbonate 22 0.14 1.38 (KHCO3) 3 Non crystallizing 7142 44.64 446.38 Sorbitol Solution 4 Glycerin 6400 40.00 400.00 5 Water 2207 13.79 137.94 6 Plasdone K29/32 100 0.63 6.25 7 Hydroxyethyl cellulose 50 0.31 3.13 8 Masking Bitter Flavor 29 0.18 1.81 Total (mg) 16000 100.00 1000.00

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, Glycerin, Potassium     -   Bicarbonate and Diclofenac in a glass container and stir until         complete dissolution;     -   Transfer the total quantity of water in a glass container and         dissolve the Plasdone K29/32 and the Hydroxyethyl cellulose;     -   Mix the two preparations obtained as above described and stir         until a homogeneous solution is obtained;     -   Add the flavor maintaining the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 3 months Time 3 months Tentative 25° C., 60% RH 30° C., 65% RH 40° C., 75% RH PFS DK 91 - bkT038/176 specifications Time zero Stick Pack Stick Pack Stick Pack Appearance of the solution Colourless Complies Complies Complies Complies clear solution pH (on sample, as it is) To be defined 8.05 8.46 8.39 8.17 Diclofenac K Assay (%) 95.0-105.0 100.4 99.8  99.7  99.3 Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — 0.234 Total (known and unknown) NMT 1.0 — — — 0.234 impurities (%)

Example 24 Liquid Oral Solution with Diclofenac, Sorbitol and Glycerin without Nitrogen (Prototype PFS DK 92-bkT038/178)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 16 g of formula; Sorbitol and Glycerin are here mixed to obtain the formula, in a different ratio in comparison to Example 23. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.31 3.13 2 Potassium Bicarbonate 22 0.14 1.38 (KHCO3) 3 Non crystallizing 5000 31.25 312.50 Sorbitol Solution 4 Glycerin 8400 52.50 525.00 5 Water 2349 14.68 146.81 6 Plasdone K29/32 100 0.63 6.25 7 Hydroxyethyl cellulose 50 0.31 3.13 8 Bitter Masking 29 0.18 1.81 Total (mg) 16000 100.00 1000.00

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, Glycerin, Potassium Bicarbonate and Diclofenac in a         glass container and stir until complete dissolution;     -   Transfer the total quantity of water in a glass container and         dissolve the Plasdone K29/32 and the Hydroxyethylcellulose;     -   Mix the two preparations obtained as above described and stir         until a homogeneous solution is obtained;     -   Add the Bitter masking maintaining the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container

Analytical Evaluations

Stability data Time 3 months Time 3 months Time 3 months Tentative 25° C., 60% RH 30° C., 65% RH 40° C., 75% RH PFS DK 92 - bkT038/178 specifications Time zero Stick Pack Stick Pack Stick Pack Appearance of the solution Colourless Complies Complies Complies Complies clear solution pH (on sample, as it is) To be defined 8.22 8.39 8.41 8.02 Diclofenac K Assay (%) 95.0-105.0 98.7  99.8  100.0 99.0 Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — 0.136 Total (known and unknown) NMT 1.0 — — — 0.136 impurities (%)

Example 25 Liquid Oral Solution with Diclofenac Sorbitol and Maltitol, without Nitrogen (Prototype PFS DK 93-bkT038/180)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 16 g of formula; Sorbitol and Maltitol are here mixed to obtain the formula. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.31 3.13 2 Potassium Bicarbonate 22 0.14 1.38 (KHCO3) 3 Non crystallizing 5000 31.25 312.50 Sorbitol Solution 4 Maltitol syrup 75% 8400 52.50 525.00 5 Water 2349 14.68 146.81 6 Plasdone K29/32 100 0.63 6.25 7 Hydroxyethyl cellulose 50 0.31 3.13 8 Masking Bitter Flavor 29 0.18 1.81 Total (mg) 16000 100.00 1000.00

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, Maltitol, Potassium Bicarbonate and Diclofenac in a         glass container and stir until complete dissolution;     -   Add the half part of hydroxyethylcellulose and stir until         complete dissolution;     -   Transfer the total quantity of water in a glass container and         dissolve the Plasdone K29/32 and the half part of         hydroxyethylcellulose;     -   Mix the two preparations obtained as above described and stir         until a homogeneous solution is obtained;     -   Add the flavor maintaining the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Analytical Evaluations

Stability data Time 3 months Time 3 months Time 3 months Tentative 25° C., 60% RH 30° C., 65% RH 40° C., 75% RH PFS DK 93 - bkT038/180 specifications Time zero Stick Pack Stick Pack Stick Pack Appearance of the solution Colourless Complies Complies Complies Complies clear solution pH (on sample, as it is) To be defined 8.36 8.23 8.24 8.21 Diclofenac K Assay (%) 95.0-105.0 105.3 104.6 104.5 104.0 Impurity 1 (%) RRT = 0.38 NMT 0.2 — — — — Impurity 2 (%) RRT = 0.44 NMT 0.2 — — — — Impurity A (3) (%) RRT = 0.60 NMT 0.2 — — — — Impurity C (4) (%) RRT = 0.82 NMT 0.2 — — — — Impurity B (6) (%) RRT = 1.39 NMT 0.2 — — — — Impurity 5 (%) RRT = 1.12 NMT 0.2 — — — 0.185 Total (known and unknown) NMT 1.0 — — — 0.185 impurities (%)

Example 26 Liquid Oral Solution with Diclofenac Sorbitol and Maltitol, without Nitrogen (Prototype PFS DK 96-bkT038/187)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 16 g of formula; Sorbitol and Fructose are here mixed with thickening agents to obtain the formula. The preparation is not carried out under nitrogen.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (1000 g) 1 Diclofenac K 50 0.31 3.13 2 Potassium Bicarbonate 22 0.14 1.38 (KHCO3) 3 Non crystallizing 11420 71.38 713.75 Sorbitol Solution 4 Plasdone K29/32 100 0.63 6.25 5 Fructose 2400 15.00 150.00 6 Water 1929 12.06 120.56 7 Hydroxyethyl cellulose 50 0.31 3.13 8 Masking Bitter Flavor 29 0.18 1.81 Total (mg) 16000.0 100.0 1000.0

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, Fructose, Potassium Bicarbonate and Diclofenac in a         glass container and stir until complete dissolution;     -   Add the half part of hydroxyethylcellulose and stir until         complete dissolution;     -   Transfer the total quantity of water in a glass container and         dissolve the Plasdone K29/32 and the half part of         hydroxyethylcellulose;     -   Mix the two preparations obtained as above described and stir         until a homogeneous solution is obtained;     -   Add the flavor maintaining the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Example 27 Liquid Oral Solution with Diclofenac and Sorbitol, without Nitrogen, Under Vacuum Conditions (Prototype PFS DK 119-bkT038/211)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 12.9 g of formula; Sorbitol is here mixed with Polyvinylpyrrolidone as a thickening agent to obtain the formula. The preparation is carried out with laboratory equipment in a higher batch size compared with the previous batches, not under nitrogen but under vacuum conditions.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (2500 g) 1 Diclofenac K 50.0 0.39 9.69 2 Potassium Bicarbonate 22.0 0.17 4.26 (KHCO3) 3 Non crystallizing 12757.20 98.89 2472.33 Sorbitol Solution 4 Plasdone K29/32 70.80 0.55 13.72 Total 12900.00 100.00 2500.00

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, in the mixer tank, under vacuum conditions;     -   Add all the Plasdone K29/32 and mix at regular intervals until a         homogeneous solution is obtained, maintaining the apparatus         under vacuum conditions;     -   Add Potassium Bicarbonate and Diclofenac, mix at regular         intervals until a homogeneous solution is obtained, maintaining         the apparatus under vacuum conditions;     -   Store the solution in the selected container.

Example 28 Liquid Oral Solution with Diclofenac, Sorbitol and Flavoring Agent, without Nitrogen, Under Vacuum Conditions (Prototype PFS DK 120-bkT038/212)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 12.9 g of formula; Sorbitol is here mixed with Polyvinylpyrrolidone as thickening agent and bitter masking as flavoring agent to obtain the formula. The preparation is obtained by the addition of the flavoring agent to Prototype PFS DK 119.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (500 g) 1 Diclofenac K 50 0.39 1.94 2 Potassium Hydrogen 22 0.17 0.85 Carbonate 3 Non crystallizing 12734.2 98.71 493.57 Sorbitol Solution 4 Plasdone K29/32 70.8 0.55 2.74 5 Masking Bitter Flavor 23 0.18 0.89 Total (mg) 12900.00 100.00 500.00

Manufacturing Method

-   -   The bitter masking is added on a fraction of the prototype PFS         DK 119 and mixed until a homogeneous solution is obtained;     -   Store the solution in the selected container.

Example 29 Liquid Oral Solution with Diclofenac, Sorbitol and Glycerin, without Nitrogen, Under Vacuum Conditions (Prototype PFS DK 121-bkT038/213)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 12.2 g of formula; Sorbitol and Glycerin are here mixed with Polyvinylpyrrolidone as thickening agent to obtain the formula. The preparation is carried out with a laboratory equipment, in a higher batch size compared with the previous batches, not under nitrogen but under vacuum conditions.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (2500 g) 1 Diclofenac K 50 0.41 10.23 2 Potassium Hydrogen 22 0.18 4.50 Carbonate 3 Non crystallizing 4529 37.06 926.55 Sorbitol Solution 4 Glycerin 7548 61.77 1544.19 5 Plasdone K29/32 71 0.58 14.53 Total (mg) 12220 100.00 2500.00

Manufacturing Method

-   -   Transfer the total quantity of Glycerin, in the mixer tank,         under vacuum conditions;     -   Add all the Plasdone K29/32 and mix at regular intervals until a         homogeneous solution is obtained, maintaining the apparatus         under vacuum conditions;     -   Add the total quantity of Non crystallizing Sorbitol Solution     -   Add Potassium Bicarbonate and Diclofenac, mix at regular         intervals until a homogeneous solution is obtained, maintaining         the apparatus under vacuum conditions;     -   Store the solution in the selected container.

Example 30 Liquid Oral Solution with Diclofenac, Sorbitol, Glycerin and Flavoring Agent, without Nitrogen, Under Vacuum Conditions (Prototype PFS DK 122-bkT038/214)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 12.2 g of formula; Sorbitol and Glycerin are here mixed with Polyvinylpyrrolidone as thickening agent and bitter masking as flavoring agent to obtain the formula. The preparation is obtained by the addition of the flavoring agent to Prototype PFS DK 121.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (500 g) 1 Diclofenac K 50 0.41 2.05 2 Potassium Hydrogen 22 0.18 0.90 Carbonate 3 Non crystallizing 4520 36.99 184.94 Sorbitol Solution 4 Glycerin 7535 61.66 308.31 5 Plasdone K29/32 71 0.58 2.91 6 Masking Bitter Flavor 22 0.18 0.90 Total (mg) 12220 100.00 500.00

Manufacturing Method

-   -   The bitter masking is added on a fraction of the prototype PFS         DK 121 and mixed until a homogeneous solution is obtained;     -   Store the solution in the selected container.

Example 31 Liquid Oral Solution with Diclofenac, Sorbitol and Maltitol, without Nitrogen, Under Vacuum Conditions (Prototype PFS DK 123-bkT038/215)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 12.9 g of formula; Sorbitol and Maltitol are here mixed with Polyvinylpyrrolidone as thickening agent. The preparation is carried out with a laboratory equipment, in a higher batch size compared with the previous batches, not under nitrogen but under vacuum conditions.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (2500 g) 1 Diclofenac K 50 0.39 9.69 2 Potassium Hydrogen 22 0.17 4.26 Carbonate 3 Non crystallizing 4784 37.09 927.13 Sorbitol Solution 4 Maltitol Syrup 7973 61.81 1545.16 5 Plasdone K29/32 71 0.55 13.76 Total 12900 100.00 2500.00

Manufacturing Method

-   -   Transfer the total quantity of Maltitol, in the mixer tank,         under vacuum conditions;     -   Add all the Plasdone K29/32 and mix at regular intervals until a         homogeneous solution is obtained, maintaining the apparatus         under vacuum conditions;     -   Add the total quantity of Non crystallizing Sorbitol Solution     -   Add Potassium Bicarbonate and Diclofenac, mix at regular         intervals until a homogeneous solution is obtained, maintaining         the apparatus under vacuum conditions;     -   Store the solution in the selected container.

Example 32 Liquid Oral Solution with Diclofenac, Sorbitol, Maltitol and Flavoring Agent, without Nitrogen, Under Vacuum Conditions (Prototype PFS DK 124-bkT038/216)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 12.9 g of formula; Sorbitol and Maltitol are here mixed with Polyvinylpyrrolidone as thickening agent and bitter masking as flavoring agent to obtain the formula. The preparation is obtained by the addition of the flavoring agent to Prototype PFS DK 123.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (500 g) 1 Diclofenac K 50 0.39 1.94 2 Potassium Hydrogen 22 0.17 0.85 Carbonate 3 Non crystallizing 4775 37.02 185.08 Sorbitol Solution 4 Maltitol Syrup 7959 61.70 308.49 5 Plasdone K29/32 71 0.55 2.75 6 Masking Bitter Flavor 23 0.18 0.89 Total 12900 100.00 500.00

Manufacturing Method

-   -   The bitter masking is added on a fraction of the prototype PFS         DK 123 and mixed until a homogeneous solution is obtained;     -   Store the solution in the selected container.

Example 33 Liquid Oral Solution with Diclofenac and Sorbitol, without Nitrogen, with and without Flavoring Agent (Prototype PFS DK 125-bkT038/217 and Prototype PFS DK 126-bkT038/218)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 12.3 g of formula; the addition of Polyvinylpyrrolidone and Hydroxyethylcellulose to the formula, with and without a flavouring agent, is here evaluated. The preparation is not carried out under nitrogen.

PFS DK 125- PFS DK 126- PFS DK 125- PFS DK 126- bkT038/217 bkT038/218 bkT038/217 bkT038/218 Ingredient mg/stick pack g/bulk (500 g) 1 Diclofenac K 50.00 50.00 2.050 2.050 2 Potassium 22.00 22.00 0.900 0.900 Hydrogen Carbonate 3 Purified water 1803.00 1803.00 73.300 73.300 4 Non crystallizing 10332.00 10310.00 420.000 419.100 Sorbitol Solution 5 Plasdone K29/32 54.00 54.00 2.200 2.200 6 Hydroxyethyl 38.00 38.00 1.550 1.550 cellulose 7 Masking Bitter — 22.00 — 0.900 Flavor Total (mg) 12299.00 12299.0 500.0 500.0

Example 34 Liquid Oral Solution with Diclofenac and Sorbitol, without Nitrogen, with and without Flavoring Agent (Prototype PFS DK 127-bkT038/219 and Prototype PFS DK 128-bkT038/220)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 17.2 g of formula; the addition of Polyvinylpyrrolidone and Hydroxyethylcellulose to the formula, with and without a flavouring agent, is here evaluated. The preparation is not carried out under nitrogen.

PFS DK 127- PFS DK 128- PFS DK 127- PFS DK 128- bkT038/219 bkT038/220 bkT038/219 bkT038/220 Ingredient mg/stick pack g/bulk (500 g) Diclofenac K 50.00 50.00 1.550 1.550 Potassium Hydrogen 22.00 22.00 0.700 0.700 Carbonate Purified water 2609.00 2578.00 73.300 73.300 Non crystallizing 14410.00 14410.00 420.700 419.800 Sorbitol Solution Plasdone K29/32 76.00 76.00 2.200 2.200 Hydroxy ethyl 53.00 53.00 1.550 1.550 cellulose Masking Bitter — 31.000 — 0.900 Flavor Total (mg) 17220.00 17220.00 500.0 500.0

Example 35 Liquid Oral Solution with Diclofenac, Sorbitol and Glycerin, without Nitrogen, with and without Flavoring Agent (Prototype PFS DK 129-bkT038/221 and Prototype PFS DK 130-bkT038/222)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 12.3 g of formula; Sorbitol and Glycerin are here mixed with Polyvinylpyrrolidone and Hydroxyethylcellulose to obtain the formula, with and without a flavouring agent. The preparation is not carried out under nitrogen.

PFS DK 129- PFS DK 130- PFS DK 129- PFS DK 130- bkT038/221 bkT038/222 bkT038/221 bkT038/222 Ingredient mg/stick pack g/bulk (500 g) 1 Diclofenac K 50.00 50.00 2.050 2.050 2 Potassium 22.00 22.00 0.900 0.900 Hydrogen Carbonate 3 Purified water 1806.00 1806.00 73.400 73.400 4 Non crystallizing 3844.00 3844.00 156.250 156.250 Sorbitol Solution 5 Glycerin 6462.00 6440.00 262.700 261.800 6 Plasdone K29/32 77.00 77.00 3.150 3.150 7 Hydroxyethyl 38.00 38.00 1.550 1.550 cellulose 8 Masking Bitter — 22.00 — 0.900 Flavor Total (mg) 12299.00 12299.00 500.0 500.0

Example 36 Liquid Oral Solution with Diclofenac, Sorbitol and Glycerin, without Nitrogen, with and without Flavoring Agent (Prototype PFS DK 131-bkT038/223 and Prototype PFS DK 132-bkT038/224)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 16.1 g of formula; Sorbitol and Glycerin are here mixed with Plasdone and Hydroxyethylcellulose to obtain the formula, with and without a flavouring agent. The preparation is not carried out under nitrogen.

PFS DK 131- PFS DK 132- PFS DK 131- PFS DK 132- bkT038/223 bkT038/224 bkT038/223 bkT038/224 Ingredient mg/stick pack g/bulk (500 g) 1 Diclofenac K 50.00 50.00 1.550 1.550 2 Potassium 22.00 22.00 0.700 0.700 Hydrogen Carbonate 3 Purified water 2363.00 2363.00 73.400 73.400 4 Non 5031.00 5009.00 156.250 156.250 crystallizing Sorbitol Solution 5 Glycerin 8481.00 8481.00 263.400 262.500 6 Plasdone 101.00 101.00 3.150 3.150 K29/32 7 Hydroxyethyl 50.00 50.00 1.550 1.550 cellulose 8 Masking Bitter — 22.00 — 0.900 Flavor Total (mg) 16098.00 16098.00 500.0 500.0

Example 37 Liquid Oral Solution with Diclofenac, Sorbitol and Maltitol, without Nitrogen, with and without Flavoring Agent (Prototype PFS DK 133-bkT038/225 and Prototype PFS DK 134-bkT038/226)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 12.2 g of formula; Sorbitol and Maltitol are here mixed with Polyvinylpyrrolidone and Hydroxyethylcellulose to obtain the formula, with and without a flavouring agent. The preparation is not carried out under nitrogen.

PFS DK 133- PFS DK 134- PFS DK 133- PFS DK 134- bkT038/225 bkT038/226 bkT038/225 bkT038/226 Ingredient mg/stick pack g/bulk (500 g) 1 Diclofenac K 50.00 50.00 2.050 2.050 2 Potassium 22.00 22.00 0.900 0.900 Hydrogen Carbonate 3 Purified water 1791.00 1791.00 73.400 73.400 4 Non crystallizing 3812.50 3812.50 156.250 156.250 Sorbitol Solution 5 Maltitol syrup 6409.90 6387.90 262.700 261.800 75% 6 Plasdone K29/32 76.90 76.90 3.150 3.150 7 Hydroxyethyl 37.80 37.80 1.550 1.550 cellulose 8 Masking Bitter — 22.00 — 0.900 Flavor Total (mg) 12200.00 12200.00 500.0 500.0

Example 38 Liquid Oral Solution with Diclofenac, Sorbitol and Maltitol, without Nitrogen, with and without Flavoring Agent (Prototype PFS DK 135-bkT038/227 and Prototype PFS DK 136-bkT038/228)

The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in about 16.1 g of formula; Sorbitol and Maltitol are here mixed with Polyvinylpyrrolidone and Hydroxyethylcellulose to obtain the formula, with and without a flavouring agent. The preparation is not carried out under nitrogen.

PFS DK 135- PFS DK 136- PFS DK 135- PFS DK 136- bkT038/227 bkT038/228 bkT038/227 bkT038/228 Ingredient mg/stick pack g/bulk (500 g) 1 Diclofenac K 50.00 50.00 1.553 1.553 2 Potassium 22.00 22.00 0.683 0.683 Hydrogen Carbonate 3 Purified water 2363.00 2363.00 73.394 73.394 4 Non crystallizing 5031.00 5031.00 156.262 156.262 Sorbitol Solution 5 Maltitol syrup 8481.00 8448.0 263.418 262.393 75% 6 Plasdone K29/32 101.00 101.00 3.137 3.137 7 Hydroxyethyl 50.00 50.00 1.553 1.025 cellulose 8 Masking Bitter — 33.00 — 1.553 Flavor Total (mg) 16100.0 16100.0 500.0 500.0

Example 39 Liquid Oral Solution with Diclofenac and High Quantity of Sorbitol as Crystallizing Sorbitol Solution, without Nitrogen (Prototype PFS DK 155-bkT038/270)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula. The preparation is carried out as done for the PFS DK 34 (see Example 5) but using the Crystallizing Sorbitol Solution instead the Noncrystallizing one.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (500 g) 1 Diclofenac K 50.00 0.25 1.25 2 Potassium Bicarbonate 22.00 0.11 0.55 (KHCO3) 3 Crystallizing 19928.00 99.64 498.20 Sorbitol Solution Total 20000.00 100.00 500.00

Manufacturing Method

-   -   Transfer the total quantity of Crystallizing Sorbitol Solution         in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Example 40 Liquid Oral Solution with Diclofenac and Medium Quantity of Sorbitol as Crystallizing Sorbitol Solution, without Nitrogen (Prototype PFS DK 152-bkT038/266)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula. The preparation is carried out as done for the PFS DK 42 (see Example 6) but using the Crystallizing Sorbitol Solution instead the Noncrystallizing one.

Quali/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (500 g) 1 Diclofenac K 50.00 0.25 1.25 2 Potassium Bicarbonate 22.00 0.11 0.55 (KHCO3) 3 Crystallizing 14286.00 71.43 357.15 Sorbitol Solution 4 Water 5642.00 28.21 141.05 Total 20000.00 100.00 500.00

Manufacturing Method

-   -   Transfer the total quantity of water and Crystallizing Sorbitol         Solution in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Example 41 Liquid Oral Solution with Diclofenac and Low Quantity of Sorbitol as Crystallizing Sorbitol Solution, without Nitrogen (Prototype PFS DK 151-bkT038/265)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 20 g of formula. The preparation is carried out as done for the PFS DK 41 (see Example 7) but using the Crystallizing Sorbitol Solution instead of the non-crystallizing one.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (500 g) 1 Diclofenac K 50.00 0.25 1.25 2 Potassium Bicarbonate 22.00 0.11 0.55 (KHCO3) 3 Crystallizing 7122.00 35.61 178.05 Sorbitol Solution 4 Water 12806.00 64.03 320.15 Total 20000.00 100.00 500.00

Manufacturing Method

-   -   Transfer the total quantity of water and Crystallizing Sorbitol         Solution in a glass container;     -   Add Potassium Bicarbonate and wait for the complete dissolution         (about 5 minutes); maintain the system under stirring;     -   Add Diclofenac Potassium and wait at least 2 hours maintaining         the system under stirring;     -   Filter the solution;     -   Store the solution in the selected container.

Example 42 Liquid Oral Solution with Diclofenac and High Quantity of Sorbitol as Crystallizing Sorbitol Solution, with Polyvinylpyrrolidone—14 ml Volume, (Prototype PFS DK 153-bkT038/168)

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 18.2 g of formula. The preparation is carried out as done for the PFS DK 87 (see Example 20) but using the Crystallizing Sorbitol Solution instead the Non-crystallizing one.

Quail/Quantitative Formulation

Ingredient mg/stick pack % g/bulk (4000 g) 1 Diclofenac K 50.00 0.27 10.99 2 Potassium Bicarbonate 22.00 0.12 4.84 (KHCO3) 3 Crystallizing 18048.00 99.16 3966.59 Sorbitol Solution 4 Povidone 80.00 0.44 17.58 Total 18200.00 100.00 4000.00

Manufacturing Method

-   -   Transfer the total quantity of Non crystallizing Sorbitol         Solution, in the mixer tank, under vacuum conditions;     -   Add all the Plasdone K29/32 and mix at regular intervals until a         homogeneous solution is obtained, maintaining the apparatus         under vacuum conditions;     -   Add Potassium Bicarbonate and Diclofenac, mix at regular         intervals until a homogeneous solution is obtained, maintaining         the apparatus under vacuum conditions;     -   Store the solution in the selected container.

Example 43 Liquid Oral Solutions with Diclofenac and High Quantity of Non Crystallizing Sorbitol Solution, with Polyvinylpyrrolidone and Differ Ent Buffering Agents—14 ml Volume

The following formulation has been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac in 18.2 g of formula. The preparations is carried out as done for the PFS DK 87 (see Example 20). The changes are the quantity of Potassium Bicarbonate or the Buffering agents (Potassium Hydroxide and Sodium Bicarbonate)

Quail/Quantitative Formulations

PFS DK 146-F PFS DK 146 C PFS DK 146-E bkT038/280-F bkT038/280-C bkT038/280-E Ingredient mg/stick pack mg/stick pack mg/stick pack 1 Diclofenac 50.00 50.00 50.00 potassium 2 Potassium — — 66.00 hydrogen carbonate 3 Potassium 2.73 — — Hydroxide 4 Sodium — 44.00 — Bicarbonate 5 Sorbitol solution 18067.27 18026.00 18004.00 (non crystallizing) 6 Plasdone K29/32 80.00 80.00 80.00 Total (mg) 18200.00 18200.00 18200.00 pH 9.26 7.85 8.12

CONSIDERATIONS BASED ON THE STABILITY DATA COLLECTED

On the basis of the data collected on the manufactured prototypes, the following considerations were made. These considerations are based on the oxidative impurities and total impurities content detected for the above-described examples; for the other parameters tested, any type of significant changes have been observed. The evaluations reported refer to samples stored both in the crimped amber vials and/or in the stick packs. The two packaging types were demonstrated to be equivalent or, in some cases, the stick packs were determined to have superior stability to crimped amber vials.

Considerations:

-   -   According to the data reported in the Example 1, Diclofenac         Potassium was shown to be chemically stable for 6 months in a         Non Crystallizing Sorbitol USP solution at the accelerated         storage conditions. The oxidative impurities and the total         impurities content are within the tentative specification limits         (less than 0.2% and 1% respectively) after 6 months of storage         at accelerated storage conditions. (The 6 months accelerated         conditions have been tested only for samples stored in stick         packs).     -   On the basis of the data reported in Examples 1-4, the chemical         stability of Diclofenac Potassium seems to be better with the         higher sorbitol concentrations.     -   The chemical stability of Diclofenac potassium in the different         Sorbitol solutions seems independent of the manufacturing         method: under N2 (Examples 1) or in open air operative         conditions (Examples 5).     -   According to Examples 9-13, Diclofenac Potassium was chemically         stable also in presence of sugars other than Non Crystallizing         Sorbitol USP solution; the prototypes obtained using Xylitol         (Example 9) were stable after 6 months at all the storage         conditions tested. The prototypes obtained using Maltitol         (Example 10), Glycerin (Example 11), Erythritol (Example 12),         were stable after 6 months at all the storage conditions tested.     -   According to the data reported in the Example 14, Diclofenac         Potassium is chemically stable in a Non Crystallizing Sorbitol         USP solution, independent of the ratio between Sorbitol and         Diclofenac. The total impurities content falls within the         tentative specification limits (less than 1%) after 6 months of         storage at the accelerated conditions.     -   According to the data reported in some other Examples (i.e. 15,         22, and 25), Diclofenac Potassium is chemically stable also in         presence of sugars in combination with Non Crystallizing         Sorbitol USP solution.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. 

1-51) (canceled) 52) An oral liquid diclofenac formulation comprising: a) a therapeutically effective amount of diclofenac or a pharmaceutically acceptable salt thereof; b) from about 0.05% to about 9% of an alkalizing agent; and c) a sugar-based aqueous means. 53) The formulation of claim 52, wherein the pH is from about 7 to about
 10. 54) The formulation of claim 52, wherein the alkalizing agent is selected from the group consisting of ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, and trolamine. 55) The formulation of claim 52, wherein the alkalizing agent is bicarbonate. 56) The formulation of claim 55, wherein the alkalizing agent is potassium bicarbonate. 57) The formulation of claim 52, wherein the diclofenac is diclofenac potassium. 58) The formulation of claim 52, comprising about 50 mg of diclofenac or a pharmaceutically acceptable salt thereof in from about 8 g to about 25 g of the formulation. 59) The formulation of claim 52, comprising from about 0.1% to about 1% diclofenac or a pharmaceutically acceptable salt thereof. 60) The formulation of claim 52, wherein the diclofenac is present as diclofenac potassium and the bicarbonate is present as potassium bicarbonate. 61) The formulation of claim 52, wherein the sugar-based aqueous means comprises a sugar selected from the group consisting of mono-, di-, tri-, and tetra-saccharides and sugar alcohols and combinations thereof. 62) The formulation of claim 61, wherein the sugar-based aqueous means comprises; a) a sugar selected from the group consisting of glucose, fructose, and galactose; or b) sugar alcohols selected from the group consisting of ethylene, propylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol and polyglycitol; or c) a combination thereof. 63) The formulation of claim 52, further comprising a flavoring agent, wherein the flavoring agent is selected from the group consisting of acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate, maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, neotame, acesulfame potassium, mannitol, talin, xylitol, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, and mixtures thereof. 64) The formulation of claim 52, comprising from about 95% to about 99.85% of the sugar-based aqueous means. 65) The formulation of claim 64, wherein the sugar-based means comprises: a) from about 0% to about 95% water; and b) from about 5% to about 95% of a sugar or sugar alcohol or a combination thereof. 66) The formulation of claim 65, wherein the sugar or sugar alcohol or combination thereof comprises: a) from about 10% to about 90% sorbitol; and b) from about 10% to about 90% of xylitol, maltitol, glycerol, fructose, erythritol or a combination thereof. 67) The formulation of claim 52, wherein the sugar-based aqueous means comprises: a) from about 0% to about 40% water; and b) from about 60% to about 80% of a sugar or sugar alcohol or a combination thereof comprising: i) from about 10% to about 90% sorbitol; and ii) from about 10% to about 90% of xylitol, maltitol, glycerol, fructose, erythritol or a combination thereof. 68) The formulation of claim 52, wherein the sugar-based aqueous means comprises: a) from about 0% to about 60% water; and b) from about 40% to about 90% of sorbitol, xylitol, maltitol, glycerol, fructose, erythritol or a combination thereof. 69) The formulation of claim 52, wherein the sugar-based aqueous means comprises: a) from about 0% to about 75% water; and b) from about 25% to about 75% of xylitol. 70) The formulation of claim 52, wherein the sugar-based aqueous means comprises: a) from about 0% to about 75% water; and b) from about 25% to about 75% of maltitol. 71) The formulation of claim 52, wherein the sugar-based aqueous means comprises: a) from about 0% to about 75% water; and b) from about 25% to about 75% of glycerol. 72) The formulation of claim 52, wherein the sugar-based aqueous means comprises: a) from about 0% to about 75% water; and b) from about 25% to about 75% of fructose. 73) The formulation of claim 52, wherein the sugar-based aqueous means comprises: a) from about 0% to about 85% water; and b) from about 15% to about 45% of erythritol. 74) The formulation of claim 52, having a density of from about 1.02 to about 1.5 g/ml. 75) The formulation of claim 52, wherein the formulation comprises from about 25% to about 90% non-crystallizing sorbitol. 76) An oral liquid diclofenac formulation comprising: a) about 0.47% diclofenac potassium; b) about 0.21% potassium hydrogen carbonate; c) about 20% xylitol; d) about 0.06% sucralose; and e) water. 77) A method of treating a condition selected from pain and migraine in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the formulation of claim
 52. 78) A method of treating pain or migraine in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the formulation of claim
 60. 79) A method of treating pain and migraine in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the formulation of claim
 76. 